Topical skin care composition

ABSTRACT

A cream base for the topical application of skin care therapeutics and a process for making the cream base. In one embodiment, the therapeutic is tretinoin, hydroquinone and fluocinolone acetonide for the treatment of hyperpigmented skin conditions, such as melasma.

FIELD OF THE INVENTION

The invention relates generally to medicated skin treating compositionsand more particularly to a cream containing a medicament for thetreatment of a hyperpigmented skin condition.

BACKGROUND OF THE INVENTION

Melasma or chloasma is a common pigmentary condition that affectsprimarily women in their reproductive years. Dark, mottled(hyperpigmented) patches appear on the face and neck, especially on thecheeks and forehead. Melasma is usually triggered by hormonal activitythat is the result of pregnancy or birth control pills. Thus, thecondition is known as the “mask of pregnancy”. The condition occurs whenexcess melanin is deposited in the cells of the epidermis and dermis.Melasma can persist for long periods of time and often recurs withsubsequent pregnancies. The condition is less common among men, whoaccount for about 10% of all cases.

Standard therapy involves depigrnenting, or bleaching, the affectedareas of the skin, the use of sunscreens, and avoidance of sunlight.Hydroquinone is the most popular topical depigmenting agent.Concentrations of 5%-10% hydroquinone are very effective, but can beirritating. The chemical stability of hydroquinone formulations isimportant because hydroquinone is easily oxidized and loses potency. Themost commonly used agent usually involves a 16- to 20-week course oftherapy, and some therapies can take longer. Tretinoin (Retin-A) isanother widely used therapy for melasma.

Nevertheless, there remains a need in the art for a therapeutic approachthat would contain several medicines for the treatment of melasma in asingle composition. Moreover, it would be useful to have a therapeuticcarrier, such as a cream, that would facilitate the penetration of themedicaments into the skin.

U.S. Pat. No. 5,538,737 discloses a method of making a water-in-oilemulsion containing a pharmaceutically acceptable salt of anH₂-antagonist. The steps include dissolving the pharmaceuticallyacceptable salt in an aqueous medium to form a water portion; combiningthe water portion with an oil portion, comprising an edible oilcomprising an ester or mixed ester of glycerol and an emulsifying agentto form a water portion and oil portion matrix; then emulsifying thematrix to form the water-in-oil emulsion.

U.S. Pat. No. 5,656,672 discloses a process for preparing a water-in-oilemulsion with retinal as the active ingredient. The emulsion contains anoil phase including at least one organic solvent for retinal (such asaliphatic fatty alcohols) and optional lipophilic additives; an aqueousphase containing water and optional hydrophilic additives; and an agentfor emulsifying the aqueous phase in the oil phase. The oil phase andthe aqueous phase are independently prepared, and the aqueous phase isincorporated into the oil phase, with subsequent addition of aphase-containing retinol and its solvent.

U.S. Pat. No. 5,660,837 discloses a process for the preparation of apharmaceutical formulation in the form of an oil-in-water emulsion. Thesteps of the process include of adding the emulsion-stabilizing surfaceactive drug and an optimal conventional surfactant to a two-phase,oil-water system at room temperature; allowing the emulsion-stabilizingsurface active drug to equilibrate at an interface; adding an agentgiving isotonicity to the final formulation; and homogenizing by highpressure technique.

U.S. Pat. No. 5,976,555 discloses skin care compositions. Anoil-in-water emulsion base contains retinoids; cetearyl alcohol andcetearyl glucoside or a mixture of a polyethylene glycol ethers ofstearyl alcohol; cetyl alcohol, stearyl alcohol and mixtures thereof; alight, dry absorbable oil; and substantive, emollient oils or waxes.

U.S. Pat. No. 6,080,393 discloses a skin care composition comprising anoil-in-water emulsion with a therapeutically effective amount of aretinoid; wherein the oil phase comprising one or more oils, and aneffective amount of at least one oil-soluble antioxidant; and whereinthe composition comprises a corticosteroid.

Nevertheless, there remains a need in the art for a method of making asmoother cream base for the application of therapeutic agents for thetreatment of melasma, which will facilitate the penetration of themedicaments into the skin.

SUMMARY OF THE INVENTION

The invention provides a cream base for the topical application of skincare therapeutics and a process for making the cream base. In oneembodiment, the therapeutic is for the treatment of hyperpigmented skinconditions, such as melasma.

The process for making the cream base entails (a) mixing the hydrophiliccompounds with water to form an aqueous phase; (b) mixing thehydrophobic compounds with methylglueth and glycerin to form ahydrophobic (non-aqueous or wax) phase; then (c) mixing the hydrophilicand hydrophobic phases to one another to form a biphasic mixture; andfinally (d) adding the emulsifier to the biphasic mixture to form theemulsion. By mixing the emulsifier after the aqueous and non-aqueousphases have been mixed, the result is a smoother-textured cream thatdisappears upon application to skin, as compared to creams made byprocesses where the emulsifier was added to the aqueous or non-aqueousphases earlier in the process. Because the emulsifier is added as thefinal step, less wax is needed in making the cream, resulting in a“thinner” hydrophilic cream that disappears faster when applied to theskin, as compared to creams made by processes where the emulsifier wasadded to the aqueous or non-aqueous phases earlier in the process.Another advantage of the process of the invention is that by controllingthe temperature at which the components, including hydroquinone, areadded, the cream does not turn as brown, resulting in a morepleasing-colored product.

In one embodiment, the invention also provides a cream, which includesthe inactive ingredients butylated hydroxytoluene, cetyl alcohol, citricacid, glycerin, glyceryl stearate, magnesium aluminum silicate, methylgluceth-10, methylparaben, PEG-100 stearate, propylparaben, purifiedwater, sodium metabisulfite, stearic acid, and stearyl alcohol. Inparticular embodiments, the cream is a carrier that contains as anactive ingredient fluocinolone acetonide, hydroquinone, tretinoin andcombinations thereof. For example, the cream can be Tri-Luma™ Cream,which is the first approved product to combine the standard depigmentingagent, hydroquinone, with tretinoin and a topical low-potency steroidthat can be applied as a single preparation. The recommended course oftherapy for Tri-Luma™ Cream is 8 weeks, and significant results havebeen seen after the first 4 weeks of treatment.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, approximately 344.8 kg of water,15.0 kg magnesium aluminum silicate, and 0.2 kg butylated hydroxytolueneare first combined and mixed at 75-80° C. to form the aqueous phase. Themixing can be by side scrape agitation at a fixed speed. The resultingaqueous phase is a suspension.

Second, approximately 20.0 kg of cetyl alcohol, 15.0 kg of stearic acid,20.0 kg of stearyl alcohol, 25.0 kg of methyl gluceth-10, 0.9 kg ofmethylparaben, 0.1 kg of propylparaben, and 20.0 kg of glycerin aremixed together at medium speed at about 75-80° C. to form thenon-aqueous phase. The mixing can be at medium speed in a Lightnin®mixer. The resulting non-aqueous phase is a suspension. The second stepcan be performed before, after or concurrently with the first step.

Then, the non-aqueous phase is added to the aqueous phase and thecombined biphasic mixture is cooled to a temperature in the range of 68°C. to 72° C., or about 70° C., after which about 17.5 kg of Arlacel®165, 0.25 kg tretinoin and 0.050 kg fluocinolone acetonide are added andstirred with cooling. When the mixture reaches 60° C., 0.25 kg citricacid is added with mixing and cooling. When the temperature reaches 55°C., 20.0 kg hydroquinone is added with mixing and cooling. When thetemperature reaches about 50° C., the mixture is homogenized with ahomogenizer, with continued cooling. When the mixture reaches 45° C.,1.0 kg of sodium metabisulfite is added with stirring and cooling.Typically, the sodium metabisulfite is added about 30 minutes after theaddition of the hydroquinone. The mixing can be at fixed speed in a sidescrape agitator. The resulting composition of matter is an emulsion,i.e., a cream.

The presence of sodium metabisulfite in the cream prevents the oxidationof hydroquinone. The addition of sodium metabisulfite as the cream iscooling advantageously results in a well-mixed composition of matter,with the sodium metabisulfite evenly mixed throughout the cream andpreventing the oxidation of the hydroquinone throughout the cream.Another advantage of the process of the invention is that by controllingthe temperature at which the components, including hydroquinone, areadded, the cream does not turn as brown, resulting in a morepleasing-colored product.

We found that the addition of the emulsifier following the mixing of thenon-aqueous and aqueous phases to be advantageous for the making of thepharmaceutical composition of the invention. When we attempted to make acream product using a standard technique of adding the emulsifier to thenon-aqueous phase and then mixing with the aqueous phase, we found thatno emulsion formed. However, when we added the emulsifier to the mixtureof the non-aqueous and aqueous phases with cooling, according to themethod of the invention, we found that a useful emulsion did form. Thisemulsion formed even though the relative proportion of the non-aqueousand aqueous phases according to the successful method of the inventionwas the same as when an emulsion did not form using the standardtechnique of adding a non-aqueous phase containing an emulsifier to anaqueous phase.

The resulting TRI-LUMA™ Cream contains fluocinolone acetonide,hydroquinone and tretinoin in a hydrophilic cream base for topicalapplication. Each gram of TRI-LUMA™ Cream contains as activeingredients, fluocinolone acetonide 0.01% (0.1 mg), hydroquinone 4% (40mg), and tretinoin 0.05% (0.5 mg), and as inactive ingredients,butylated hydroxytoluene, cetyl alcohol, citric acid, glycerin, glycerylstearate, magnesium aluminum silicate, methyl gluceth-10, methylparaben,PEG-100 stearate, propylparaben, purified water, sodium metabisulfite,stearic acid, and stearyl alcohol. See, TABLE 1.

TABLE 1 500 g Batch 800 g Batch Ingredient Quantity Quantity Formulamagnesium aluminum silicate 15 kg 24 kg  3.00% NF butylatedhydroxytoluene NF 200 g 320 g  0.04% cetyl alcohol NF 20 kg 32 kg  4.00%stearic acid NF 15 kg 24 kg  3.00% stearyl alcohol NF 20 kg 32 kg  4.00%methylparaben NF 900 g 1,440 g  0.18% propylparaben NF 100 g 160 g 0.02% Arlacel ® 165 [glycerol stearate 17.5 kg 28 kg  3.50% and PEG-100stearate glycerol monostearate] methyl gluceth-10 25 kg 40 kg  5.00%glycerin USP 20 kg 32 kg  4.00% tretinoin USP 250 g 400 g  0.05%fluocinolone acetonide USP 50 g 80 g  0.01% citric acid USP 250 g 400 g 0.05% hydroquinone USP 20 kg 32 kg  4.00% sodium metabisulfite NF 1 kg1.6 kg  0.20% purified water USP 344.8 kg 551.6 kg  68.95% total 100.00%

Fluocinolone acetonide is a synthetic fluorinated corticosteroid fortopical dermatological use and is classified therapeutically as ananti-inflammatory. It is a white crystalline powder that is odorless andstable in light. The chemical name for fluocinolone acetonide is(6,11,16)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]-pregna-1,-4-diene-3,20-dione.The molecular formula is C₂₄H₃₀F₂O₆ and molecular weight is 452.50.

Hydroquinone is classified therapeutically as a depigmenting agent. Itis prepared from the reduction of p-benzoquinone with sodium bisulfite.It occurs as fine white needles that darken on exposure to air. Thechemical name for hydroquinone is 1,4-benzenediol. The molecular formulais C₆H₆O₂ and molecular weight is 110.11.

Tretinoin is all-trans-retinoic acid formed from the oxidation of thealdehyde group of retinene to a carboxyl group. It is highly reactive tolight and moisture. Tretinoin is classified therapeutically as akeratolytic. The chemical name for tretinoin is:(all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoicacid. The molecular formula is C₂₀H₂₈O₂ and molecular weight is 300.44.

TRI-LUMA™ Cream is typically supplied in 30 g aluminum tubes, NDC0299-5950-30, and is stored at controlled room temperature 68 to 77° F.(20-25° C.).

The details of one or more embodiments of the invention are set forth inthe accompanying description above. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, the preferred methods andmaterials are now described. Other features, objects, and advantages ofthe invention will be apparent from the description and from the claims.In the specification and the appended claims, the singular forms includeplural referents unless the context clearly dictates otherwise. Unlessdefined otherwise, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this invention belongs. All patents and publications citedin this specification are incorporated by reference.

The following EXAMPLES are presented to more fully illustrate thepreferred embodiments of the invention. These EXAMPLES should in no waybe construed as limiting the scope of the invention, as defined by theappended claims.

EXAMPLE I Human Pharmacokinetics

Percutaneous absorption of unchanged tretinoin, hydroquinone andfluocinolone acetonide into the systemic circulation of two groups ofhealthy volunteers (Total n=59) was found to be minimal following 8weeks of daily application of 1 g (Group I, n=45) or 6 g (Group II,n=14) of TRI-LUMA™ Cream.

For tretinoin quantifiable plasma concentrations were obtained in 57.78%(26 out of 45) of Group 1 and 57.14% (8 out of 14) of Group II subjects.The exposure to tretinoin as reflected by the C_(max) values ranged from2.01 to 5.34 ng/mL (Group I) and 2.0 to 4.99 ng/mL (Group II). Thus,daily application of TRI-LUMA™ Cream resulted in a minimal increase ofnormal endogenous levels of tretinoin. The circulating tretinoin levelsrepresent only a portion of total tretinoin-associated retinoids, whichwould include metabolites of tretinoin and that sequestered intoperipheral tissues.

For hydroquinone quantifiable plasma concentrations were obtained in 18%(8 out of 44) Group I subjects. The exposure to hydroquinone asreflected by the C_(max) values ranged from 25.55 to 86.52 ng/mL. AllGroup II subjects (6 g dose) had undetectably low post-dose plasmaconcentrations.

For fluocinolone acetonide, Groups I and II subjects had undetectablylow post-dose plasma concentrations.

The following tests may be helpful in evaluating patients: (a) ACTH orcosyntropin stimulation tests; (b) the A.M. plasma cortisol test; and(c) the urinary free cortisol test.

EXAMPLE II Human Clinical Studies

Two efficacy and safety studies were conducted in 641 melasma patientsbetween the ages of 21 to 75 years, having skin phototypes I-IV andmoderate to severe melasma of the face. TRI-LUMA™ Cream was comparedwith three possible combinations of two of the three active ingredients[(1) hydroquinone 4% (HQ)+tretinoin 0.05% (RA); (2) fluocinoloneacetonide 0.01% (FA)+tretinoin 0.05% (RA); (3) fluocinolone acetonide0.01% (FA)+hydroquinone 4% (HQ)], contained in the same vehicle asTRI-LUMA™ Cream.

The patients were instructed to apply their study medication each night,after washing their face with a mild soapless cleanser, for 8 weeks. Thepatients were also instructed to apply a thin layer of study medicationto the hyperpigmented lesion, making sure to cover the entire lesionincluding the outside borders extending to the normal pigmented skin.The patients were provided a mild moisturizer for use as needed and asunscreen with SPF 30 for daily use. Moreover, the patients wereinstructed to avoid sunlight exposure to the face, wear protectiveclothing Protective clothing and avoidance of sunlight exposure to theface was recommended.

The patients were evaluated for melasma seventy at baseline and at weeks1, 2, 4, and 8 of treatment. Primary efficacy was based on theproportion of patients who had an investigators' assessment of treatmentsuccess, defined as the clearing of melasma at the end of the eight-weektreatment period. The majority of patients enrolled in the two studieswere white (approximately 66%) and female (approximately 98%). TRI-LUMA™Cream was demonstrated to be significantly more effective than any ofthe other combinations of the active ingredients.

Patients experienced improvement of their melasma with the use ofTRI-LUMA™ Cream as early as 4 weeks. However, among 7 patients who hadclearing at the end of 4 weeks of treatment with TRI-LUMA™ Cream, 4 ofthem did not maintain the remission after an additional 4 weeks oftreatment.

After 8 weeks of treatment with the study drug, patients entered into anopen-label extension period in which TRI-LUMA™ Cream was given on anas-needed basis for the treatment of melasma. In studies, after 8 weeksof treatment with TRI-LUMA™ Cream, most patients had at least someimprovement. Some had their dark spots clear up completely (38% in onestudy and 13% in another). In most patients treated with TRI-LUMA™Cream, their melasma came back after treatment. The remission periodsappeared to shorten between progressive courses of treatment.Additionally, few patients maintained complete clearing of melasma(approximately 1 to 2%).

TABLE 2 Investigators' Assessment of Treatment Success* At the End of 8Weeks of Treatment TRI-LUMA ™ Cream HQ + RA FA + RA FA + HQ Study No. 1Number of 85 83 85 85 Patients Number of 32 12  0  3 SuccessesProportion of 38% 15%  0%  4% Successes P-value <0.001 <0.001 <0.001Study No. 2 Number of 76 75 76 78 Patients Number of 10  3  3  1Successes Proportion of 13%  4%  4%  1% Successes P-value^(#)  0.045 0.042  0.005 *Treatment success was defined as melasma severity scoreof zero (melasma lesions cleared of hyperpigmentation). ^(#)P-value isfrom Cochran-Mantel-Haenszel chi-square statistics controlling forpooled investigator and comparing TRI-LUMA ™ Cream to the othertreatment groups.

Based on melasma severity at the beginning of the trial, 161 patientswere assessed for improvement at day 56 of treatment. 61% (99 patients)experienced symptom improvement from “moderate” to “mild” or “cleared”,and 68% (25) showed improvement from “severe” to “mild” or “cleared”over the 8-week treatment period as shown in TABLE 3.

TABLE 3 Investigators' Assessment of Change in Melasma Severity fromBaseline to Day 56 of Treatment (combined results from studies 1 and 2)Baseline Number (%) of Patients at Day 56^(a) Severity Cleared^(b)Mild^(b) Moderate^(b) Severe^(b) Missing^(b) Rating N N (%) N (%) N (%)N (%) N (%) Tri-Luma ™ Moderate 124 36 (29) 63 (51) 18 (16) 0 (0) 7 (6%)Cream Severe 37  6 (16) 19 (51)  9 (24) 2 (5) 1 (3%) N = 161^(a)Assessment based on patients with severity scores at day 56.Percentages are based on the total number in the treatment grouppopulation. ^(b)Does not include patients who cleared before day 56 orwere missing from the day 56 assessment. Assessment scale: Cleared(melasma lesions approximately equivalent to surrounding normal skin orwith minimal residual hyperpigmentation); Mild (slightly darker than thesurrounding normal skin); Moderate (moderately darker than thesurrounding normal skin); Severe (markedly darker than the surroundingnormal skin).

EXAMPLE III Averse Reactions in Humans

In a patch test study to determine sensitization potential in 221healthy volunteers, three volunteers developed sensitivity reactions toTRI-LUMA Cream or its components.

In the controlled clinical trials, adverse events were monitored in the161 patients who used TRI-LUMA™ Cream once daily during an 8-weektreatment period. There were 102 (63%) patients who experienced at leastone treatment-related adverse event during these studies. The mostfrequently reported events were erythema, desquamation, burning,dryness, and pruritus at the site of application. The majority of theseevents were mild to moderate in severity. Adverse events reported by atleast 1% of patients and judged by the investigators to be reasonablyrelated to treatment with TRI-LUMA™ Cream from the controlled clinicalstudies are summarized (in decreasing order of frequency) as follows:

TABLE 4 Incidence and Frequency of Treatment-Related Adverse Events withTRI-LUMA ™ Cream In At Least 1% or More of Patients (N = 161) AdverseEvent Number (%) of Patients Erythema 66 (41%)  Desquamation 61 (38%) Burning 29 (18%)  Dryness 23 (14%)  Pruritus 18 (11%)  Acne 8 (5%)Paresthesia 5 (3%) Telangiectasia 5 (3%) Hyperesthesia 3 (2%) Pigmentarychanges 3 (2%) Irritation 3 (2%) Papules 2 (1%) Acne-like rash 1 (1%)Rosacea 1 (1%) Dry mouth 1 (1%) Rash 1 (1%) Vesicles 1 (1%)

In an open-label long-term safety study, patients who have hadcumulative treatment of melasma with TRI-LUMA™ Cream for 6 months showeda similar pattern of adverse events as in the 8-week studies. Thefollowing local adverse reactions have been reported infrequently withtopical corticosteroids. They may occur more frequently with the use ofocclusive dressings, especially with higher potency corticosteroids.These reactions are listed in an approximate decreasing order ofoccurrence: burning, itching, irritation, dryness, folliculitis,acneiform eruptions, hypopigmentation, perioral dermatitis, allergiccontact dermatitis, secondary infection, skin atrophy, striae, andmiliaria.

The foregoing description has been presented only for the purposes ofillustration and is not intended to limit the invention to the preciseform disclosed, but by the claims appended hereto.

1. A method of making a topical medicated composition comprising water,hydrophilic compounds and hydrophobic compounds, and active ingredientsconsisting of fluocinolone acetonide, hydroquinone and tretinoin, themethod comprising: (a) mixing water and at least one hydrophiliccompound to form an aqueous composition; (b) mixing at least twohydrophobic compounds to form a non-aqueous composition; (c) mixing theaqueous composition and the non-aqueous composition to form a mixture,said steps (a) through (c) being conducted in the absence of anemulsifier; (d) mixing the fluocinolone acetonide and the tretinoin intothe mixture of step (c); (e) adding at least one emulsifier after step(c) into the mixture of step (c), or during step (d); and thereafter (f)homogenizing the mixture; wherein the hydroquinone is added in step (d)after adding the at least one emulsifier.
 2. The method of claim 1,wherein said aqueous composition comprises, magnesium aluminum silicateand butylated hydroxytoluene.
 3. The method of claim 1, wherein saidnon-aqueous composition comprises at least two hydrophobic compoundsselected from the group consisting of cetyl alcohol, stearic acid,stearyl alcohol, methyl gluceth, methylparaben, propylparaben andglycerin.
 4. The method of claim 3, wherein said non-aqueous compositioncomprises cetyl alcohol, stearic acid, stearyl alcohol, methyl gluceth,methylparaben, propylparaben and glycerin.
 5. The method of claim 1,wherein said at least one emulsifier is glyceryl stearate, polyethyleneglycol (PEG) stearate or a combination thereof.
 6. The method of claim5, wherein said at least one emulsifier is a combination of glycerylstearate and polyethylene glycol stearate.
 7. The method of claim 1,further comprising adding sodium metabisulfite to said mixture of step(e) after adding said at least one emulsifier.
 8. The method of claim 1,wherein said water and said at least one hydrophilic compound are mixedat an elevated temperature.
 9. The method of claim 8, wherein saidelevated temperature is from about 75° C. to about 80° C.
 10. The methodof claim 1, wherein said at least two hydrophobic compounds are mixed atan elevated temperature.
 11. The method of claim 10, wherein saidelevated temperature is from about 75° C. to about 80° C.
 12. The methodof claim 1, wherein said water and said at least one hydrophiliccompound are mixed at a temperature of from about 75° C. to about 80°C., and said at least two hydrophobic compounds are mixed at atemperature of from about 75° C. to about 80° C.
 13. The method of claim12, wherein said mixture of step (c) is cooled before adding saidfluocinolone acetonide and said tretinoin in step (d).
 14. The method ofclaim 13, wherein said cooled temperature is from about 68° C. to about72° C.
 15. The method of claim 12, wherein said mixture of step (d) iscooled while the at least one emulsifier is mixed into the mixture ofstep (d).
 16. The method of claim 12, wherein the hydroquinone is addedin step (d) after the mixture of tretinoin and fluocinolone acetonide iscooled.
 17. The method of claim 16, wherein said mixture is cooled toabout 55° C. before adding said hydroquinone.
 18. The method of claim12, wherein said homogenizing step (f) occurs at a temperature of about50° C.
 19. The method of claim 18, wherein sodium metabisulfite is addedto the homogenized mixture after the hydroquinone is added and after thehomogenized mixture is cooled to about 45° C.
 20. A method of making atopical medicated composition comprising water, hydrophilic compoundsand hydrophobic compounds, and active ingredients consisting offluocinolone acetonide, hydroquinone and tretinoin, the methodcomprising: (a) mixing water and at least one hydrophilic compound toform an aqueous composition comprising magnesium aluminum silicate andbutylated hydroxytoluene; (b) mixing at least two hydrophobic compoundsto form a non-aqueous composition, wherein the hydrophobic compounds areselected from the group consisting of cetyl alcohol, stearic acid,stearyl alcohol, methyl gluceth, methylparaben, propylparaben, andglycerin; (c) mixing the aqueous composition and the non-aqueouscomposition to form a mixture, said steps (a) through (c) beingconducted in the absence of an emulsifier; (d) mixing the fluocinoloneacetonide and the tretinoin into the mixture of step (c); (e) adding atleast one emulsifier after step (c) into the mixture of step (c), orduring step (d); and thereafter (f) homogenizing the mixture; whereinthe hydroquinone is added in step (d) after adding the at least oneemulsifier.
 21. The method of claim 20, wherein at least one emulsifieris glyceryl stearate, polyethylene glycol (PEG) stearate or acombination thereof.